The present invention relates to novel sulfur-containing fused pyrimidine derivatives useful as medicines.
Autacoids which are produced in vivo and exhibit various pharmacological actions in the small amounts thereof which are liberated from cells by stimulation of some kind, and act on cells and organs in the vicinity of production sites thereof to play an important role in the expression, the maintenance and the regulation of various physiological functions.
Vascular endothelial cells produce various biologically active substances, thereby regulating vasoactivity and hemocyte functions. In particular, prostacyclin (PGI.sub.2) and endothelium-derived relaxation factors (EDRF) have been noted as factors for relaxing vascular smooth muscles. It has recently been found that one of the endothelium-derived relaxation factors is nitrogen monoxide (NO) or an analogue thereof.
On the other hand, it was also reported that the endothelial cells produced the factors for constricting vascular smooth muscles (ECOF) under various stimulation conditions such as anoxia. In 1988, M. Yanagisawa et al. succeeded in isolating a vasoconstrictor substance from the culture supernatant of the endothelial cells of porcine aortae [M. Yanagisawa et 1., Nature 332, 411 (1988)]. This substance, consisting of 21 amino acid residues and 2 intramolecular disulfide bonds, was named "endothelin (ET)". The endothelin strongly contracts various smooth muscles (such as tracheal smooth muscles) including vascular smooth muscles (such as coronary arteries, aortae and basilar arteries) of animals including human. The activities are strong more than 10 times as strong as those of known constrictor peptides such as angiotensin II, vasopressin and neuropeptide Y, and it is not affected by receptor antagonists or synthetic inhibitors of known vasoactive substances such as serotonin, norepinephrine, thromboxane A.sub.2 and leukotriene. It is known that only calcium antagonists partially inhibit their activities. It has recently become clear that the endothelin has not only smooth muscle constrictor activity, but also various physiological activities. For example, the endothelin promotes secretion of atrial natriuretic peptides in cultured rat atrial muscles, and inhibits renin secretion from juxtaglomerular cells. However, it is not entirely revealed till now what physiological role endothelin plays in vivo and what pathology endothelin is concerned with. Considering the various activities of the endothelin and the distribution of endothelin receptors over a wide range from vascular vessel systems to brains, the endothelin might relate to various diseases such as renal, pulmonary and cardiac diseases. It is further anticipated that the endothelin acts as a hormone or an autacoid controling circulation or as a neurotransmitter.
Nerve growth factor (NGF) is a polypeptide having 118 amino acids. NGF is a neurotrophic factor necessary for differentiation and survival in peripheral, sensory and central neurons In the brain, NGF is distributed in cerebral cortex and hippocampus, and acts as a neurotrophic factor for cholinergic neurons in basal forebrain. In the case of patients suffering from Alzheimer's disease, degeneration of cholinergic neurons in basal forebrain is significantly involved, and it is believed that impairment of learning and memory of the disease is due to this degeneration [M. Goedert et al., Mol. Brain Res., 1, 85-92 (1986)]. Recently, it has been reported that in various animal models with cerebral lesion NGF prevents the degeneration of cholingergic neurons and improves the impairment of learning and memory [F. Hefti, J. Neuroscience, 6, 2155-2162 (1986); V. Pallage, Brain Res., 386, 197-208 (1986)]. From these findings, NGF draws an attention as the most effective candidate for the treatment of Alzheimer's disease.
On the other hand, interleukin-1 (IL-1) known as an inflammatory autacoid is produced and secreted mainly in stimulated monocytes or macrophages. Recently, it has been shown that Il-1 can be produced by many types of cells including endothelial cells or fibroblasts.
Furthermore, IL-1 acts on various types of cells and is involved in many functions. First, relating to immune or inflammatory reactions, it makes lymphocytes, T and B cells, to differentiate or to proliferate increasing their production of cytokines such as IL-2 of CSFs. It acts on endothelial cells and play important roles in fibrinogenesis or lymphocyte adhesion, and acts on hepatocytes to make acute phase proteins. Second, it relates to connective tissue cells. It causes fibroblast or synovial cells to proliferate. However, it induces protease production and reduce the extracellular matrix proteins on these cells causing tissue damages. Similarly, it acts on chondrocytes or bone cells. Third, the action of IL-1 on nervous cells is also becoming clear.